Epidemiological studies have shown that Asian Indians (AI) are insulin resistant (IR) and at risk for diabetes and coronary artery disease (CAD) when compared to Caucasians (C) of northern European ancestry. The increased risk of CAD in AI is not explained by the traditional risk factors like hypertension and lipid abnormalities suggesting that other factors play a role. A preliminary study by our group demonstrated that compared to C matched for body mass index (BMI) and age, AI were more IR and had altered body fat distribution. Recently there has been considerable interest in the role of insulin resistance in the pathogenesis of other physiological disorders, including endothelial dysfunction. Independent data suggests that IR states like obesity, type 2 diabetes and as well as young normoglycemic IR first degree relatives of diabetics have endothelial dysfunction. Based on these data, this project has its primary goal to test the hypothesis that healthy AI have IR, altered body fat distribution and endothelial dysfunction compared to C matched for age and BMI. We also hypothesize that Al have greater endothelial dysfunction compared to C with similar degrees of insulin resistance. The secondary goal is to determine whether insulin sensitizers can improve IR and endothelial dysfunction in AI compared to C. We hypothesize that reversing insulin resistance using insulin sensitizers will correct endothelial dysfunction to a lesser degree in AI when compared to C with comparable insulin resistance. Healthy AI, C, and first degree relatives of Caucasian diabetics matched for BMI and age will undergo euglycemic hyperinsulinemic clamp to assess IR, brachial artery ultrasound to asses endothelial function in the basal and insulin stimulated states, CT scan to measure abdominal fat. It is anticipated that AI will be IR and have decreased endothelium dependent vasodilation in the basal and insulin stimulated states. AI will have greater degree of endothelial dysfunction compared to C with similar degrees of IR. The ability of the insulin sensitizers to improve IR and endothelial function will be examined in both AI and C. Subjects will be placed on pioglitazone for 16 weeks and will undergo all the tests done for the initial study. It is anticipated that there will be a substantial improvement of IR, endothelial function, and body fat distribution in Al compared to C matched for age and BMI. When compared to C with similar IR, we expect that AI will have lesser degree of improvement of their endothelial function, reflecting the presence of residual vascular dysfunction that contributes to their excess risk of CAD. There may be a substantial benefit to understand the underlying mechanism of IR and endothelial dysfunction in AI. This will enable us to initiate specific therapy to prevent diabetes and CAD in this ethnic group. Expertise and teaching from my mentors and a rich research environment at the Brigham & Women's Hospital will enable me to become an independent physician scientist.